Apixaban Prevents Strokes, Boosts Survival in Afib Patients

Action Points

Explain that apixaban, an oral factor Xa inhibitor, was compared to dose adjusted warfarin in subjects with atrial fibrillation.

Note that in the primary outcome of hemorrhagic or ischemic stroke or systemic embolization, apixaban was superior to warfarin.

Note that apixaban had a lower rate of major bleeding and a lower rate of death from any cause than warfarin.

PARIS -- Compared with warfarin treatment, atrial fibrillation patients treated with the investigational factor Xa inhibitor apixaban had fewer strokes or embolic events, fewer major bleeding events, and were less likely to die during an average of almost two years of treatment, researchers said.

Those results emerged from the 18,201-patient ARISTOTLE study, which was published online today by the New England Journal of Medicine.

"The primary outcome of stroke or systemic embolism occurred in 212 patients in the apixaban group (1.2% per year) as compared with 265 patients in the warfarin group (1.60% per year)," Christopher B. Granger, MD, of the Duke Clinical Research Institute at Duke University Medical Center in Durham, N.C., and colleagues wrote.

Additionally, the hazard ratio in the apixaban group was 0.79 (95% CI 0.66 to 0.95; P<0.001 for noninferiority and P=0.01 for superiority.

The benefit was largely driven by the difference in hemorrhagic stroke -- 0.24% per year for apixaban (40 strokes) versus 0.47% (78 strokes) for warfarin (HR 0.51, 95% CI 0.35-0.75, P<0.001). The rate of ischemic stroke was similar in both arms of the trial, 0.9% per year with apixaban and 1.05% per year with warfarin (P=0.42).

The authors concluded that the lower risk of hemorrhagic stroke "suggests there is a specific risk associated with warfarin, possibly related to its inhibition of multiple coagulation factors or interaction between warfarin and tissue factor VIIa complexes in the brain."

The median age of patients in ARISTOTLE was 70, and all had at least one additional risk factor for stroke. About a fourth of the patients were treated at centers in North America and 40% were treated at European centers. The rest of the clinical sites were in South America or the Asian Pacific.

Background therapies included ACE inhibitors or ARBs in about 70% of patients, as well as beta-blockers (63-64%), statins (45%), and aspirin (31%). About 41% of patients had normal creatinine clearance, and 42% had mildly impaired creatinine clearance.

The 9,120 patients in the apixaban arm received 5 mg bid (2.5 mg in selected patients) while warfarin patients were treated to target (international normalized ratio [INR], 2.0 to 3.0). Blinding was assured with sham INR testing in the apixaban arm.

On average the warfarin patients had INRs in therapeutic range 62% of the time.

In addition to publication in NEJM, the ARISTOTLE results were reported at the European Society of Cardiology meeting during a Hot Line session today.

Asked about the results, Elliott Antman, MD, professor of medicine at Harvard Medical School, and a spokesperson for the American Heart Association, called the trial results "not only a home run, but an out of the park home run."

Indeed, when compared with the other emerging oral agents -- dabigatran (Pradaxa), which is FDA approved for stroke prevention in patients with atrial fibrillation, and rivaroxaban (Xarelto), which is approved for prevention of DVT in patients undergoing joint replacement surgery -- apixaban does have some advantages.

For example, rivaroxaban, which is also a direct factor Xa inhibitor, demonstrated that it was not inferior to warfarin, but it did not demonstrate superiority to warfarin in the intention-to-treat analysis from ROCKET-AF. And a pivotal trial that compared dabigatran with warfarin found higher rates of myocardial infarction, gastric distress, and dyspnea among patients treated with dabigatran.

But in an NEJM editorial, Jessica L. Mega, MD, MPH, of Harvard Medical School in Boston, wrote that dabigatran (150 mg bid) is the only one of the three agents to have "significantly reduced the risk of ischemic stroke compared with warfarin."

Mega noted that a third direct factor Xa inhibitor (edoxaban) is currently being tested in the ENGAGE study, which is being conducted by her colleagues at Brigham and Woman's Hospital (including Antman, who is the principal investigator for that study).

Nonetheless, she wrote that warfarin is unlikely to be swept away by the new agents because although it does require INR monitoring and dietary restrictions -- it easily beats any of competitors on cost, estimated at $4.00 a month compared with as much as $160/month for dabigatran.

Ralph Brindis, MD, a cardiologist at Kaiser Permanente in Oakland, Calif., and immediate past president of the American College of Cardiology, said the ARISTOTLE results were "just another stake or dagger in the heart of warfarin for prevention stroke."

He said, however, that as good as the apixaban numbers were, they won't necessarily translate into a big win when -- or if -- the FDA approves the drug.

A potential downside of these new drugs is that it is not possible to monitor adherence. No need for blood tests could make the drugs very appealing to patients, but for clinicians that is not necessarily the case since "one of the strengths of warfarin is that we know the patient is adhering because we are getting the blood tests," he explained.

Granger said his institution received grant money from Bristol-Myers Squibb, and he received consulting fees or honoraria from Pfizer and Bristol-Myers Squibb. Additionally, he reported paid consultancies with Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, and The Medicines Company. He said he has grants or pending grants with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medtronic Foundation, Medtronic Foundation, Merck & Co., Sanofi-Aventis, The Medicines Co., and Astellas. Finally, he reported travel grants from Medtronic and Merck.

Mega said she has worked as consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, and Sanofi-Aventis. She has received research funding or has grants pending with Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, and Sanofi-Aventis.

Antman is a principal investigator of ENGAGE AF-TIMI 48 a phase III trial of the oral factor Xa inhibitor edoxaban, which is being developed by Daiichi Sankyo.